Unique roles of ATAC and SAGA - KAT2A complexes in normal and malignant hematopoiesis

Abstract

Epigenetic histone modifiers are key players in cell fate decisions. Significant research hasfocused on their enzymatic activity, but less is known about the contextual role of the complexes they integrate. We focus on KAT2A, a histone acetyltransferase we recently associated with leukemia stem cell maintenance, and which participates in ATAC and SAGA complexes. We show that ATAC is uniquely required for maintenance of normal and leukemia stem and progenitor cells, while SAGA more specifically contributes to cell identity. This dichotomy sets a paradigm for investigating epigenetic activities in their macromolecular context and informs epigenetic regulator targeting for translational purposes.

The related coactivator complexes SAGA and ATAC control embryonic stem cell self-renewal through acetyltransferase-independent mechanisms

“…Inactivation of SAGA decreased the expression of genes related to LIF signaling, whereas ATAC depletion affected the expression of genes related to cytoplasmic translation such as RPGs. Thus, each complex makes use of its specific activities to regulate different sets of genes, eventually leading to self-renewal defects of mouse ESCs, in agreement with previous studies in Drosophila or differentiated human cells (Arede et al, 2020;Gamper et al, 2009;Krebs et al, 2011;Nagy et al, 2010;Pankotai et al, 2005Pankotai et al, , 2010.…”

Gene Transcription as a Therapeutic Target in Leukemia

“…KAT2A exhibits its acetyltransferase activity in the context of two macromolecular complexes, Spt-Ada-Gcn5-acetyltransferase (SAGA) and Ada-Two-A-Consing (ATAC) [ 111 ]. Both complexes contribute to the spread of leukemia and affect certain aspects of metabolism and proliferation (ATAC), as well as cell identity and survival (SAGA), together explaining the need for KAT2A in LSCs [ 113 ]. KAT2A inhibition induces differentiation and apoptosis in AML cells but not in normal progenitors [ 114 ], thereby serving as a promising avenue for drug development.…”